Computational study of fluoroquinolone binding to and its applicability to future drug design

Fluoroquinolones are an important therapeutic class in the targeting of new and resistant bacterial infections. Fluoroquinolones bind to bacterial type II topoisomerase via a water‐Mg²⁺ bridge. However, binding to magnesium‐containing molecules outside of the target cells increases the minimum inhibitory concentration (MIC) and promotes drug resistance. As a result, fluoroquinolones are counter‐indicated with magnesium and multivalent metal cation containing drugs, such as antacids. The antibiotic efficacy of fluoroquinolones has also been shown to be pH dependent, as we show the effect of protonation state on magnesium binding. This work presents a systematic computational study of fluoroquinolones' magnesium‐binding properties. We use B3LYP density functional theory and triple‐zeta basis sets, to evaluate binding affinities. Complexation is predicted to be thermodynamically favorable at neutral and basic compared to acidic pH. The calculated complexation energies broadly capture experimental binding affinities, suggesting this is a valid approach for designing new fluoroquinolones with a target magnesium binding affinity. We also investigate the effect of chemical substitution at the carboxylic acid to help in the identification of potential new antibiotics based on the fluoroquinolone pharmacophore.     

Self‐Pillared,Single‐Unit‐Cell Sn‐MFI Zeolite Nanosheets and Their Use for Glucose and Lactose Isomerization

Single‐unit‐cell Sn‐MFI, with the detectable Sn uniformly distributed and exclusively located at framework sites, is reported for the first time. The direct, single‐step, synthesis is based on repetitive branching caused by rotational intergrowths of single‐unit‐cell lamellae. The self‐pillared, meso‐ and microporous zeolite is an active and selective catalyst for sugar isomerization. High yields for the conversion of glucose into fructose and lactose to lactulose are demonstrated.     

Polymicrobial Biofilm Inhibition Effects of Acetate‐Buffered Chitosan Sponge Delivery Device

Polymicrobial biofilm‐associated implant infections present a challenging clinical problem. Through modifications of lyophilized chitosan sponges, degradable drug delivery devices for antibiotic solution have been fabricated for prevention and treatment of contaminated musculoskeletal wounds. Elution of amikacin, vancomycin, or a combination of both follows a burst release pattern with vancomycin released above minimum inhibitory concentration for Staphylococcus aureus for 72 h and amikacin released above inhibitory concentrations for Pseudomonas aeruginosa for 3 h. Delivery of a vancomycin, amikacin, or a combination of both reduces biofilm formation on polytetrafluoroethylene catheters in an in vivo model of contamination. Release of dual antibiotics from sponges is more effective at preventing biofilm formation than single‐loaded chitosan sponges. Treatment of pre‐formed biofilm with high‐dose antibiotic release from chitosan sponges shows minimal reduction after 48 h. These results demonstrate infection‐preventive efficacy for antibiotic‐loaded sponges, as well as the need for modifications in the development of advanced materials to enhance treatment efficacy in removing established biofilm.

     

Quantification of copper and zinc species fractions in legume seeds extracts by SEC/ICP-MS: validation and uncertainty estimation

Fractions of Cu and Zn species in legume samples (common white bean, pea, chick pea and lentil seeds and defatted soybean flour) were analysed by on-line hyphenation of size exclusion chromatography and inductively coupled plasma-mass spectrometry. Samples were extracted by 0.02 mol l⁻¹ Tris–HCl buffer solution, pH 7.5. The extraction efficiency lay in the region 60–90 and 60–80% for Cu and Zn, respectively. Quantification of elements in the individual chromatographic fractions was carried out by isotope dilution (ID) and external calibration (EC) techniques. For ID analysis the chromatographic effluent was mixed with the flow of ⁶⁵Cu and ⁶⁸Zn isotope enriched solution and the isotope ratio values ⁶³Cu/⁶⁵Cu and (⁶⁴Zn+⁶⁶Zn)/⁶⁸Zn were measured. In the case of EC technique calibration solutions of elements were injected to the flow of mobile phase by the second injector. Prior entering detector the effluent was mixed with the flow of internal standard solution (In, 50 μg l⁻¹). Both methods have similar precision, however the behaviour of both studied elements was not the same. The chromatographic analysis itself was the main source of variability in the case of Cu. For Zn species analysis, the extraction process and the manipulation with the extract, played the significant role too. It was probably caused by lower stability of the present zinc chelates. The total amounts of Zn found in all chromatographic fractions represented 85–95% of Zn in sampled extract whereas those of Cu approached 100%. In case of small peaks the results of ID and EC were not the same. The EC results were lower then ID results. The great deal of results uncertainty accounts for the precision.     

Alteration of foliar flavonoid chemistry induced by enhanced UV-B radiation in field-grown Pinus ponderosa, Quercus rubra and Pseudotsuga menziesii

Chromatographic analyses of foliage from several tree species illustrate the species-specific effects of UV-B radiation on both quantity and composition of foliar flavonoids. Pinus ponderosa, Quercus rubra and Pseudotsuga menziesii were field-grown under modulated ambient (1x) and enhanced (2x) biologically effective UV-B radiation. Foliage was harvested seasonally over a 3-year period, extracted, purified and the flavonoid fraction applied to a mu Bondapak/C(18) column HPLC system sampling at 254 nm. Total flavonoid concentrations in Quercus rubra foliage were more than twice (leaf area basis) that of the other species; Pseudotsuga menziesii foliage had intermediate levels and P. ponderosa had the lowest concentrations of total flavonoids. No statistically significant UV-B radiation-induced effects were found in total foliar flavonoid concentrations for any species; however, concentrations of specific compounds within each species exhibited significant treatment effects. Higher (but statistically insignificant) levels of flavonoids were induced by UV-B irradiation in 1- and 2-year-old P. ponderosa foliage. Total flavonoid concentrations in 2-year-old needles increased by 50% (1x ambient UV-B radiation) or 70% (2x ambient UV-B radiation) from that of 1-year-old tissue. Foliar flavonoids of Q. rubra under enhanced UV-B radiation tended to shift from early-eluting compounds to less polar flavonoids eluting later. There were no clear patterns of UV-B radiation effects on 1-year-old P. menziesii foliage. However, 2-year-old tissue had slightly higher foliar flavonoids under the 2x UV-B radiation treatment compared to ambient levels. Results suggest that enhanced UV-B radiation will alter foliar flavonoid composition and concentrations in forest tree species, which could impact tissue protection, and ultimately, competition, herbivory or litter decomposition.     

Benzenoid ring contractions in the thermal automerization of acenaphthylene

Acenaphthylene-1-¹³C (1) rearranges at high temperatures in a flow system to give acenaphthylene-5-¹³C (2) and acenaphthylene-4-¹³C (3) in a 1:1 ratio as the primary products. This apparent migration of a labeled carbon atom from the bridge to the most remote sites in the molecule can be understood in terms of a benzenoid ring contraction mechanism.     

Relative effectiveness of pretreatments on performance of Rhizomucor miehei lipase in nonpolar reaction media

Enzymes can be used in nonpolar reaction media to modify waterinsoluble substrates. A variety of pretreatments, applied to the enzyme prior to introduction to the nonpolar media, can improve enzyme activity. However, the various pretreatments have not been studied using directly comparable conditions, nor have they been applied simultaneously to test for interactive effects. This work evaluates pretreatment of lipase with various classes of additives. The pretreated lipase is used to catalyze esterification between citronellol and acetic acid in a medium of n-hexane. The effectiveness of a particular pretreatment is presented in terms of relative performance (RP), which is equal to the number of times faster the pretreated lipase catalyzes the reaction relative to untreated lipase. The individual and interactive effects of the pretreatment factors were studied and compared. Buffer salts had a much stronger performance-enhancing effect than nonbuffer salts; pretreatment with 90% (w/w) sodium phosphate yielded lipase with an RP of approx 64. A strong interaction was found between the treatments with sodium phosphate and pH adjustment. These treatments may mitigate the inhibitory effect of acetic acid. Activating effects of phase interfaces and active-site protectants are shown to be complementary to other treatments, demonstrating that they likely act by distinct mechanisms.     

Bis{2,6‐bis[3‐(2,4,6‐trimethylphenyl)pyrazol‐1‐yl‐κN2]pyridine‐κN}zinc(II) diperchlorate bis(nitromethane) solvate

The title compound, [Zn(C₂₉H₂₉N₅)₂](ClO₄)₂·2CH₃NO₂, contains a Zn^II ion showing only small deviations from local D_2d symmetry. The lower rhombicity exhibited by this complex compared with that of its Cu^II congener suggests that the highly rhombic stereochemistry exhibited by the latter is largely imposed by the stereoelectronic preferences of the Cu^II ion.     

Critical evaluation of electrode design and matrix effects on monitoring organophosphate pesticides using composite carbon nanotube-modified electrodes

Carbon nanotubes (CNT)/Nafion-modified glassy carbon (GC) electrodes were used to immobilize the enzyme acetylcholinesterase (AChE) by crosslinking with glutaraldehyde. The CNT-modified electrodes exhibited a sensitive and stable electrocatalytic behavior towards thiocholine (TCh). Compared to ordinary GC electrodes modified with Nafion, a substantial (500-mV) decrease in the overvoltage of the TCh oxidation reaction is observed, along with a tenfold enhancement in the amperometric response. The CNT/Nafion/AChE electrode has very good stability of at least a month compared to surfaces made without crosslinking in the absence and presence of Nafion. Under optimal loadings of CNT, Nafion, AChE, and glutaraldehyde, a solution of CNT/Nafion in N,N-dimethylformamide (DMF) containing 4 mg/mL CNT and 0.01% Nafion was used to construct the electrodes in order to maximize the sensitivity of the biosensor for inhibition studies. An optimal enzyme loading of 0.137 U and crosslinking in 0.01% glutaraldehyde for 1 h was also needed to achieve this goal. The prepared electrodes had very good reproducibility to 1.0 mM acetylthiocholine (ATCh) (relative standard deviation [RSD] <5% for eight electrodes). Using paraoxon as a model pesticide, the biosensor was able to detect as low as 1.0 nM after 30 min of incubation at 30 °C. Using a log scale, the biosensor had good linearity in the concentration range 50?C800 nM, with a correlation coefficient of 0.99. The prepared biosensor was used to test real water samples spiked with paraoxon and showed good correlation with a calibration curve using phosphate buffer.